The matrix metalloproteases (also known as matrix metalloendo-proteinases or MMPs) are a family of zinc endoproteinases which include, but are not limited to, interstitial collagenase (also known as MMP-1), stromelysin (also known as proteoglycanase, transin, or MMP-3), gelatinase A (also known as 72kDa-gelatinase or MMP-2) and gelatinase B (also known as 95 kDa-gelatinase or MMP-9). These MMPs are secreted by a variety of cells including fibroblasts and chondrocytes, along with natural proteinatious inhibitors known as TIMPs (Tissue Inhibitor of MetalloProteinase).
All of these MMPs are capable of destroying a variety of connective tissue components of articular cartilage or basement membranes. Each MMP is secreted as an inactive proenzyme which must be cleaved in a subsequent step before it is able to exert its own proteolytic activity. In addition to the matrix destroying effect, certain of these MMPs such as MMP-3 have been implicated as the in vivo activator for other MMPs such as MMP-1 and MMP-9 (Ito, A. and Nagase, H., Arch. Biochem. Biophys., 26, 211-6 (1988); Ogata, Y.; Enghild, J. and Nagase, H., J. Biol. Chem. 267, 3581-4 (1992)). Thus, a cascade of proteolytic activity can be initiated by an excess of MMP-3. It follows that specific MMP-3 inhibitors should limit the activity of other MMPs that are not directly inhibited by such inhibitors.
It has also been reported that MMP-3 can cleave and thereby inactivate the endogenous inhibitors of other proteinases such as elastase (Winyard, P. G.; Zhang, Z.; Chidwick, K.; Blake, D. R.; Carrell, R. W.; Murphy, G., FEBS Lett. 279 91-4 (1991). Inhibitors of MMP-3 could thus influence the activity of other destructive proteinases by modifying the level of their endogenous inhibitors.
A number of diseases are thought to be mediated by excess or undesired matrix-destroying metalloprotease activity or by an imbalance in the ratio of the MMPs to the TIMPs. These include: a) osteoarthritis (Woessner, J. F., Jr.; Selzer, M. G., J. Biol. Chem. 259, 3633-8 (1984) and Phadke, K., J. Rheumatol. A, 852-60 (1983)), b) rheumatoid arthritis (Mullins, D. E.; Rohrlich, S. T., Biochim. Biophys. Acta 695 117-214 (1983); Woolley, D. E.; Crossley, M. J.; Evanson, M. J., Arthritis Rheum. 20, 1231-9 (1977); and Gravallese, E. M.; Darling, J. M.; Ladd, A. L.; Katz, J. N.; Glimcher, L. H., Arthritis Rheum. 3, 1076-84 (1991)), c) septic arthritis (Williams, R. J., III; Smith, R. L.; Schurman, D. J., Arthritis Rheum. 33, 533-41 (1990)), d) tumor metastasis (Reich, R.; Thompson, E. W.; Iwamoto, Y.; Martin, G. R.; Deason, J. R.; Fuller, G. C.; Miskin, R., Cancer Res. 48, 3307-12 (1988) and Matrisian, L. M.; Bowden, G. T.; Krieg, P.; Fuerstenberger, G.; Briand, J. P.; Leroy, P.; Breathnach, R., Proc. Natl. Acad. Sci. U.S.A. 83, 9413-7 (1986)), e) periodontal diseases (Overall, C. M.; Wiebkin, O. W.; Thonard, J. C. J. Peridontal. Res. 22, 81-8 (1987)), f) corneal ulceration (Burns, F. R.; Stack, M. S.; Gray, R. D.; Paterson, C. A., Invest. Ophthalmol. Vis. Sci. 30, 1569-75 (1989)), g) proteinuria (Baricos, W. H.; Murphy, G.; Zhou, Y.; Nguyen, H. H.; Shah, S. V., Biochem. J. 254, 609-12 (1988)), h) coronary thrombosis from atherosclerotic plaque rupture (Davies, M. J.; Foster, K.; Hembry, R.; Murphy, G.; Humphries, S., Proc. Natl. Acad. Sci. U.S.A. 88, 8154-8) (1991)), i) aneurysmal aortic disease (Vine, N.; Powell, J. T., Clin. Sci. 81, 233-9 (1991)), j) birth control (Woessner, J. F., Jr.; Morioka, N.; Zhu, C.; Mukaida, T.; Butler, T.; LeMaire, W. J., Steroids 54, 491-9 (1989)), k) dystrophobic epidermolysis bullosa (Kronberger, A.; Valle, K. J.; Eisen, A. Z.; Bauer, E. A., J. Invest. Dermatol. 79, 208-11 (1982)), and 1) degenerative cartilage loss following traumatic joint injury, conditions leading to inflammatory responses, osteopenias mediated by MMP activity, tempero mandibular joint disease, demyelating diseases of the nervous system, etc. (Chantry, A.; Earl, C.; Groome, N.; Glynn, P., J. Neurochem. 50, 688-94 (1988)).
The need for new therapies is especially important in the case of arthritic diseases. The primary disabling effect of osteoarthritis (OA), rheumatoid arthritis (AR) and septic arthritis is the progressive loss of articular cartilage and thereby normal joint function. No marketed pharmaceutical agent is able to prevent or slow this cartilage loss, although nonsteroidal antiinflammatory drugs (NSAIDs) have been given to control pain and swelling. The end result of these diseases is total loss of joint function which is only treatable by joint replacement surgery. MMP inhibitors are expected to halt or reverse the progression of cartilage loss and obviate or delay surgical intervention.
Proteases are critical elements at several stages in the progression of metastatic cancer. In this process, the proteolytic degradation of structural protein in the basal membrane allows for expansion of a tumor in the primary site, evasion from this site as well as homing and invasion in distant, secondary sites. Also, tumor induced angiogenesis is required for tumor growth and is dependent on proteolytic tissue remodeling. Transfection experiment with various types of proteases have shown that the matrix metalloproteases, in particular, gelatinases A and B (MMP-2 and MMP-9, respectively) play a dominant role in these processes. For an overivew of this field see Mullins, D. E.; Rohrlich, S. T., Biochim. Biophys. Acta 695, 177-214 (1983); Ray, J. M.; Stetler-Stevenson, W. G., Eur. Respir. J. 7, 2062-72 (1994) and Birkedal-Hansen, H.; Moore, W. G. I.; Bodden, M. K.; Windsor, L. J.; Birkedal-Hansen, B.; DeCarlo, A.; Englar, J. A., Crit. Rev. Oral. Biol. Med. 4, 197-250 (1993).
Furthermore, it could be shown that inhibition of degradation of extracellular matrix by the native matrix metalloprotease inhibitor TIMP-2 (a protein) arrests cancer growth (De Clerck, Y. A.; Perez, N.; Shimada, H.; Boone, T. C.; Langley, K. E.; Taylor, S. M., Cancer Res. 52, 701-8 (1992)) and that TIMP-2 inhibits tumor-induced angiogenesis in experimental systems (Moses, M. A.; Sudhalter, J.; Langer, R., Science 248, 1408-10 (1990)). For a review see De Clerck, Y.; Shimada, H.; Taylor, S. M.; Langley, K. E., Ann. N. Y. Acad. Sci. 732, 222-32 (1994). It was also demonstrated that the synthetic matrix metalloprotease inhibitor batimastat when given intraperitoneally inhibits human colon tumor growth and spread in an orthotopic model in nude mice (Wang, X.; Fu, X.; Brown, P. D.; Crimmin, M. J.; Hoffman, R. M. Cancer Res. 54, 4726-8 (1994)) and prolongs the survival of mice bearing human ovarian carcinoma xenografts (Davies, B.; Brown, P. D.; East, N.; Crimmin, M. J.; Balkwill, F. R., Cancer Res. 53, 2087-91 (1993)). The use of this and related compounds has been described in WO-A-9321942.
There are several patents and patent applications disclosing the use of metalloproteinase inhibitors for the retardation of metastatic cancer, promoting tumor regression, inhibiting cancer cell proliferation, slowing or preventing of cartilage loss associated with osteoarthritis or for treatment of other diseases as indicated above (e.g. WO-A-9519965; WO-A-9519956; WO-A-9519957; WO-A-9519961; WO-A-9321942; WO-A-9321942; WO-9421625; U.S. Pat. No. 4,599,361; U.S. Pat. No. 5,190,937; EP 0574 758 A1, published Dec. 22, 1993; EP 026 436 A1 published Aug. 3, 1988; and EP 0520 573 A1, published Dec. 30, 1992). The preferred compounds of these patents have peptide backbones with a zinc complexing group (hydroxamic acid, thiol, carboxylic acid or phosphinic acid) at one end and a variety of side chains, both those found in the natural amino acids as well as those with more novel functional groups. Such small peptides are often poorly absorbed, exhibiting low oral bioavailability. They are also subject to rapid proteolytic metabolism, thus having short half lives. As an example, batimastat, the compound described in WO-A-9321942, can only be given intraperitoneally.
WO 9615096, published 23 May, 1996 describes substituted 4-biarylbutyric or 5-biarylpentanoic acids and derivatives as matrix metalloprotease inhibitors. This is a continuation-in-part of U.S. application Ser. No. 08/339,846, filed Nov. 15, 1994, which was incorporated by reference. The application discloses two substituted 4-biphenyl-4-hydroxybutyric acid derivatives (examples 33 and 34, shown below). These compounds are less potent as MMP-3 inhibitors than the corresponding 4-biphenyl-4-oxobutyric acid derivatives. ##STR2##
It is desirable to have effective MMP inhibitors which possess improved bioavailabilty and biological stability relative to the peptide-based compounds of the prior art, and which can be optimized for use against particular target MMPs. Such compounds are the subject of the present application.